We face a global health crisis sparked by an epidemic in obesity and metabolic syndrome. Over 34% of US adults suffer from metabolic syndrome and therefore experience increased risk for cardiovascular disease, type 2 diabetes, inflammation and infection. Direct health care costs arising from obesity and/or related disorders account for 7-10% of all US health care expenditures annually. Mounting evidence has implicated the gut microbiota in obesity and metabolic syndrome. Our long-term goal is to discover natural compounds that can modulate immune function and capitalize on that knowledge to develop cost-effective complementary treatments to improve human health. Our objectives in this project are to determine mechanisms by which vitamin D and xanthohumol from the hops plant mediate regulation of innate immunity, improve gut barrier function, alter microbiota composition and reduce manifestations of obesity and metabolic syndrome. Our central hypothesis is that xanthohumol and vitamin D each induce expression of cathelicidin antimicrobial peptide (CAMP) in mucosal epithelia and improve gut epithelial barrier function, reduce inflammation, modify the structure and function of the gut microbiota, and ultimately reduce overweight/obesity and MetS. Our rationale is that, once we establish that we can reproducibly manipulate the composition and function of the microbiota with these two agents, development of new and innovative approaches to prevent and/or treat obesity and related disorders would be possible. We propose three Specific Aims: 1) determine the contribution of gut microbiota to efficacy of oral xanthohumol and/or vitamin D treatment of diet-induced obesity; 2) determine the mechanism by which vitamin D and/or xanthohumol alter the gut microbiota composition/function and reduce diet induced obesity and 3) determine efficacy of vitamin D and/or xanthohumol to improve gut barrier defense and reduce susceptibility of obese mice to infection. We expect this study to elucidate how interactions between bioactive compounds, host factors, and the gut microbiome will integrate to impact the effect of complementary treatment for inflammatory and metabolic disorders that impact millions of lives and add billions of dollars to healthcare costs worldwide.